FORMULATION AND IN-VITRO EVALUATION OF · PDF fileJalpeshkumar D. Bhavsar*, Mukesh R. Patel, Kanu R. Patel, N.M.Patel Shri B. M. Shah College of Pharmaceutical Education & Research,

Vol-3, Issue-4, Suppl-1, Nov 2012 ISSN: 0976-7908 Bhavsar et al

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PHARMA SCIENCE MONITOR

AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

FORMULATION AND IN-VITRO EVALUATION OF MUCOADHESIVE

BUCCAL TABLET OF FAMOTIDINE

Jalpeshkumar D. Bhavsar*, Mukesh R. Patel, Kanu R. Patel, N.M.Patel

Shri B. M. Shah College of Pharmaceutical Education & Research, College Campus, Dhansura Road, Modasa, Dist. Sabarkantha, 383350, Gujarat, India.

ABSTRACT Famotidine is histamine –H2 receptor antagonist. It has bioavailability of 40 to 45% and it has shorter plasma half-life of 2.5 to 3.5 hrs. The effective treatment of erosive esophagitis and Zolinger-Elisons syndrome requires administration of 20 mg of Famotidine 4 times a day. A conventional dose of 20 mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. An alternative dose of 40 mg leads to plasma fluctuations; thus a sustained release dosage form of famotidine is desirable. Direct access to the systemic circulation bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Moreover, the buccal route is easily accessible, has a good patient compliance and can be used in patients who can’t swallow. Bilayer buccal tablet was prepared by using mucoadhesive polymers combination of Sodium CMC and Carbopol934P, by direct compression with backing layer of Ethyl cellulose. The formulation was optimized by 32 full factorial statistical design by selecting independable variables Ratio of polymer as factor X1 and Concentration of polymer as factor X2. The prepared formulations were evaluated for various evaluation studies. Statistical analysis as well as kinetic studies performed. Statistical study showed that both factors X1 and X2 had significant effect on dependable variables Q4 (P=0.005), Q8 (P=0.013), Mucoadhesive strength (P=0.000) and Swelling index (Except factor X1 for swelling index) (P=0.001). Formulation F1 was selected as an optimum formulation as it shows more similarity in dissolution profile with theoretical profile (f2 = 65.76 and f1 = 7.04). The optimized formulation F1 had given release of 102.57% in 8hrs and it had optimum swelling, mucoadhesive property and permeation from buccal mucosa. It also had desired drug release kinetics and found to be stable for the period of 1 month. Keywords: Buccal tablet, Swelling index, Bioadhesive strength, Famotidine. INTRODUCTION

After oral administration many drugs are subjected to presystemic clearance extensive in

liver, which often leads to a lack of significant correlation between membrane

permeability, absorption, and bioavailability. Difficulties associated with parenteral

delivery and poor oral availability provided the impetus for exploring alternative routes

for the delivery of such drugs. These include routes such as pulmonary, ocular, nasal,

rectal, buccal, sublingual, vaginal, and transdermal. Among the various transmucosal



routes, buccal mucosa has excellent accessibility, an expanse of smooth muscle and

relatively immobile mucosa, hence suitable for administration of retentive dosage forms.

Direct access to the systemic circulation through the internal jugular vein bypasses drugs

from the hepatic first pass metabolism leading to high bioavailability [1].

Buccal route is advantageous due to, No hepatic first-pass effect, No pre-systemic

metabolism in the gastrointestinal tract, Ease of administration, Fast onset of action, No,

or little, irritation expected, Patient compliance, Low enzymatic activity, Painless

administration, Easy drug withdrawal, Facility to include permeation enhancer/enzyme

inhibitor or pH modifier in the formulation, Versatility in designing as multidirectional or

unidirectional release systems for local or systemic actions [2].

Famotidine is a competitive inhibitor of histamine H2-receptors. Primary clinically

important pharmacological activity of famotidine is inhibition of gastric secretion [3].

Both the acid concentration and volume of basal, nocturnal and stimulated gastric

secretion are suppressed by famotidine. It is commonly used in benign gastric ulcer,

duodenal ulcer, Gastro esophageal reflux disease and Zolinger-Elisons syndrome. It has

bioavailability of 40 to 45% due to extensive first pass metabolism and peak plasma

reaches within 1 to 3 hrs. It has a half-life of 2.5 to 3.5 hours [4]. The effective treatment

of erosive esophagitis and Zolinger-Elisons syndrome requires administration of 20 mg

of Famotidine 4 times a day [5]. A conventional dose of 20 mg can inhibit gastric acid

secretion up to 5 hours but not up to 10 hours. An alternative dose of 40 mg leads to

plasma fluctuations; thus a sustained release dosage form of famotidine is desirable.

Rationale for development of this formulation is improvement of bioavailability by

avoiding first pass metabolism through buccal delivery of drug; More absorption of drug

due to pka value of 7.1 which gives more unionized species for absorption at pH between

6.8 to 7.4 in buccal region; Low molecular weight (<500 D) of drug also contributes to

permeability of it through buccal mucosa; Half life of drug between 2.5 to 3.4 hr

promotes for sustained delivery of drug through buccal mucosa; Develop formulation

with unidirectional drug release.

MATERIALS AND METHODS

Materials



Famotidine was received as a gift sample from Panchsheel organics ltd. (Ahmedabad,

India). Sodium Carboxy methyl cellulose and Carbopol 934P were purchased from Loba

chemie ltd. (Mumbai, India). Lactose were purchased from Finar Chemicals Ltd.

(Ahmedabad, India). Aspartame were provided from college. All ingredients used in

study are of analytical grade.

Formulation of mucoadhesive buccal tablet:

Direct double compression technique was employed for the formulation. In this

technique, first intermediate layer was formed and blend of second layer was placed on

first intermediate layer and compressed to get bilayer tablet (Figure 1). Compositions of

the core layer contain drug, mucoadhesive polymers (carbopol-934P, Sodium carboxy

methyl cellulose), lactose, Aspartame and lubricant, for backing layer ethyl cellulose

was used. The physical blend of drug, polymers and excipients was properly mixed and

passed through 60 mesh screen, and then it was slightly compressed by using 8 mm flat

faced punch in Rimek 10 station rotary press to obtain intermediate tablet or loose

compact. Similarly, blend of backing layer containing ethyl cellulose was mixed, sieved

and compressed on the previously compressed intermediate tablet or loose compact to

get bilayer tablet. The hardness of the obtained tablets was found 6-7 kg/cm2.

.

Bilayer buccal tablet. EXPERIMENTAL DESIGN:

A 32 randomized full factorial design was employed in the present study. In this design 2

factors were evaluated, each at 3 levels, and experimental trials were performed for all 9

possible combinations. The ratio of polymer (Sodium CMC: Carbopol 934P) (X1) and

concentration of polymer (X2) were chosen as independent variables in 32 full factorial

design, while Q4, Q8 (% drug release after 4, 8 hours respectively), % swelling index,

Bioadhesive strength, diffusion coefficient (n), release rate constant (K) were taken as



dependent variables. The composition of factorial design batches (F1-F9) is shown in

Table 1 and Table 2. The prepared formulations were evaluated for in vitro release study,

Swelling index, Bioadhesive strength, in vitro residence time, Surface pH, hardness,

friability, drug content, weight variation test. Statistical treatment was carried out to the

factorial design batches using statistica software.

TABLE 1: CODING OF VARIABLE

32 Full factorial design

X1 Polymer ratio (Sodium CMC: Carbopol 934P)

X2 Polymer concentration

Levels

-1 1:2

Levels

-1 15%

0 1:1 0 20%

1 2:1 1 25%

TABLE 2: FORMULATION OF FACTORIAL BATCHES

Formulation Code F1 F2 F3 F4 F5 F6 F7 F8 F9

Ingr

edie

nts

(m

g)

Famotidine 20 20 20 20 20 20 20 20 20

Sodium CMC 5 8 10 7 10 13 8 13 17

Carbopol 934P 10 8 5 13 10 7 17 13 8

Lactose 60 60 60 55 55 55 50 50 50

Magnesium Stearate

1 1 1 1 1 1 1 1 1

Talc 1 1 1 1 1 1 1 1 1

Aspartame 2 2 2 2 2 2 2 2 2

Ethyl Cellulose 50 50 50 50 50 50 50 50 50

Total weight in mg 150 150 150 150 150 150 150 150 150

CHARACTERIZATION OF BUCCAL TABLET:

Drug Excipient Compatibility Study:

Ø FTIR Spectral studies:

Drug- excipients interactions play a vital role in the release of drug from formulation.

Fourier transform infrared spectroscopy has been used to study the physical and chemical

interactions between drug and the excipients used. Fourier transform infrared (FTIR)

spectra of Famotidine and mixture of Famotidine: Sodium carboxy methyl cellulose:



Carbopol 934P were recorded using KBr mixing method on FTIR instrument of the

institute.

Ø Differential Scanning Calorimeter (DSC):

Thermograms were obtained by using differential scanning calorimeter at a heating rate

20°C/min. over a temperature range of 50-300°C by using instrument DSC instrument.

The sample was hermetically sealed in an aluminum crucible. Thermograms of drug and

formulation were compared for any disappearance or shifting in characteristic peak of

drug melting point.

Weight Variation Test [6]:

Twenty tablets were selected at random, weighed and the average weight was calculated.

Not more than two of the individual weights should deviate from the average weight by

more than 7.5 % as per IP.

Friability [6]:

For each formulation, pre weighed tablet sample (20 tablets) were placed in the Roche

friabilator which is then operated for 100 revolutions. The tablets were deducted and

reweighed. Conventional compressed tablets that loose <1% of their weight are

considered acceptable.

Hardness [6]:

Hardness of tablet was determined using Monsanto hardness tester.

Content Uniformity [6]:

Twenty tablets were weighed and powdered in a glass mortar. Quantity of powder

equivalent to 20 mg of Famotidine was accurately weighed and transferred to 100 ml pH

6.8 phosphate buffer in volumetric flask. From the resulting solution 10 ml of the sample

was withdrawn and adjusted final volume in volumetric flask up to 100 ml using pH 6.8

phosphate buffer. The solution was analyzed at λmax value of 272 nm by using UV-

Visible spectrophotometer. The content of drug was calculated from calibration curve.

In Vitro Swelling or Swelling Index [7]:

This test was carried out by using Petri dishes having 10 ml of phosphate buffer of pH 6.8

and tablet was placed in Petri dish. The initial weights of the drug loaded tablets in each

batch were determined (W0) using an electronic balance. Tablets from each batch were



removed at different time intervals (1, 2, 3, 4, 6 and 8 hrs), wiped with filter paper to

remove excess water from the tablet surface, and then reweighed (W1). The swelling

index (% w/w) was determined from the following relationship and plotted against time.

The experiment was performed in triplicate. (Eq.1)

Swelling index (1)

In Vitro Mucoadhesive strength test [8]:

Mucoadhesive strength of the buccal tablets was measured by using the modified

physical balance. The test assembly was fabricated as shown in schematic presentation

(Figure 1). This method involves the use of goat buccal mucosa as the model mucosal

membrane. The fresh goat buccal mucosa was purchased from slaughter house and it was

then washed in isotonic phosphate buffer pH 6.8. The two sides of the balance were

balanced with a 5 gm weight on the right hand side. A piece of fresh membrane was

glued to a support (glass block) with cyanoacrylate adhesive. The block was then lowered

into the glass container, which was then filled with isotonic phosphate buffer pH 6.8 kept

at 37± 1 °C, such that the buffer just reaches the surface of mucosal membrane, and keeps

it moist. This was then kept below the left hand setup of the balance. The test

mucoadhesive tablet was glued with the same adhesive to a rubber block hanging on the

left hand side and the balance beam raised with the 5 gm weight on the right pan was

removed off the weight. This lowered the rubber block along with the tablet over the

mucosa with a weight of 5 gm. The balance was kept in this position for 3 minutes and

then slowly water was added to the plastic container in the right pan by pipette. The

detachment of two surfaces was obtained. Weight of water was measured. Then the

Mucoadhesive strength of tablet was calculated. Three tablets were tested on each goat

buccal mucosal membrane. After each measurement, the tissues were gently and

thoroughly washed with phosphate buffer pH 6.8 and left for 5 minutes before the next

experiment. Fresh membrane was used for each batch of tablets. The experiment was

performed in triplicate.



Figure 1 Modified balance assembly for in vitro mucoadhesive strength test

1. Rubber block

2. Mucoadhesive tablet

3. Glass block

4. pH 6.8 phosphate buffer

5. Buccal mucosa

In Vitro Residence time test [9]:

The in vitro residence time is one of the most important physical parameters of buccal

tablet. A buccal tablet was pressed over the excised goat buccal mucosa for 30 sec after

previously being secured on a glass slide and was immersed in a beaker containing 500

ml of pH 6.8 isotonic phosphate buffer, at 37±0.2°C. One stirrer was fitted at a distance

of 5 cm from the tablet and rotated at 25 rpm. The time for complete erosion or

detachment of the tablet from the mucosa was recorded.

Surface pH measurement [7]:

The buccal tablets were first allowed to swell by keeping them in contact with 5 ml of pH

6.8 phosphate buffer for 2 hrs. The surface pH was then found by bringing a combined

glass electrode near the surface of the tablets and allowing the reading to stabilize for at

least 1 min. The measurements were taken in triplicate for each batch of the buccal

tablets.

In Vitro Dissolution study [7]:



The USP type II rotating paddle method was used to study the drug release from the

bilayer tablet. The dissolution medium consisted of 500 ml of pH 6.8 phosphate buffer.

The release study was performed at 37 ± 0.5°C, with a rotation speed of 50 rpm. The

backing layer of the buccal tablet was attached to the glass slide with cyanoacrylate

adhesive. The disk was placed at the bottom of the dissolution vessel. Aliquots were

withdrawn at regular time intervals and replaced with fresh medium to maintain sink

conditions. The samples were filtered, made appropriate dilutions with phosphate buffer

and were thereafter analyzed spectrophotometrically at λmax value of 272 nm using a

Shimadzu UV-Visible1800 double-beam spectrophotometer. Cumulative percentage drug

release was calculated using an equation obtained from a calibration curve which was

developed in the range of 5-35µg/ml for pH-6.8 phosphate buffer. The experiment was

performed in triplicate.

Ex vivo permeation study [10]:

Figure 2 Ex vivo permeation study by Franz-diffusion apparatus

The fresh goat buccal mucosal membrane was obtained from slaughter house. It was than

excised by removing the underlying connective and adipose tissue and was equilibrated at

37 ± 1.0 C for 30 min in pH 6.8 isotonic phosphate buffer. The buccal epithelium was



carefully mounted in between the two compartments of Franz Diffusion Cell. Tablets

were stuck to the mucosa in the donor side containing pH 6.8 phosphate buffer. Receiver

medium was 20 ml of pH 6.8 phosphate buffer maintained at 37 ± 0.5 C under gentle

stirring. From the receiver compartment, 5 ml aliquots were collected at predetermined

time intervals and replaced by an amount of fresh buffer. The samples removed were

filtered, diluted and analyzed at λmax value of 272 nm using a Shimadzu UV-Visible 1800

double-beam spectrophotometer. The schematic representation of franz diffusion

apparatus was displayed in Figure 2.

Kinetic Modeling of Dissolution Data:

The dissolution profile of all batches were fitted to various models such as zero order[11],

first order[11], Higuchi [12], Korsmeyer and Peppas [13] to ascertain the kinetic of drug

release.

Comparison of Dissolution Profiles for Selection Optimum Batch [14]:

Ø Similarity factor (f2):

The similarity factor (f2) given by SUPAC guidelines for a modified release dosage

form was used as a basis to compare dissolution profiles. The dissolution profiles are

considered to be similar when f2 is between 50 and 100. The dissolution profile of

products were compared using a f2 which is calculated from following formula:

(Eq.2)

( )

−

+=

−

=∑ 10011logX50 X

5.02

12

n

tttt TRw

nf (2)

Where, n is the dissolution time and Rt and Tt are the reference (here is the theoretical

dissolution profile of Famotidine) and test dissolution value at time t respectively.

Optimized batch was compared with theoretical profile for calculation of similarity

factor.

Ø Dissimilarity factor (f1):

The dissimilarity factor (f1) calculates the percent difference between the two curves

at each time point and is a measurement of the relative error between the two curves:

(Eq.3)



100×Rt /|Tt-Rt|11

1

= ∑∑

==

n

t

n

t

nnf

(3)

Where: n is the number of time points, Rt is the dissolution value of the theoretical

dissolution profile at time t and Tt is the dissolution value of the formulation at time t.

The values should lie between 0-15. For curves to be considered similar f1 values

should be close to 0.

Stability Study of Optimized Batch:

To determine the change in physical properties and in vitro release profile on storage

optimized batch tablets were stored at 40ºC ± 5ºC and 75% ± 5% relative humidity in

stability chamber. Samples were evaluated at 1 month time for in vitro dissolution study.

RESULT AND DISCUSSION

Drug Excipient Compatibility Study

FTIR Spectral studies:

The Famotidine exhibits peaks due to sulphonamide (1331.89 cm-1), amine (3104.53 cm-

1) and alkene (719.47 cm-1, 1161.19 cm-1) groups. It was observed that there were no

changes in these main peaks in the FTIR spectra of a mixture of drug and polymers

(Figure 3). Hence, it was concluded that no physical or chemical interactions of

Famotidine with Sodium CMC, Carbopol 934P and other excipients.

400600800120016002000280036001/cm

15

30

45

60

75

90

105

120

%T

3506

.7034

00.62

3237

.63

3103

.57

1638

.58 1331

.89

1171

.7911

61.19 71

9.47

3505

.7434

00.62

3235

.70

3104

.53

1638

.58 1331

.89

1171

.7911

47.68

720.4

4Famotidine + Formulation

Smooth

Famotidine + Formulation

Figure 3 FTIR spectra of Famotidine + Formulation



Differential Scanning Calorimeter (DSC):

On comparison with thermogram of pure drug and formulation showed no shift or

disappearance of characteristic peak of drug melting point suggesting that there was no

interaction of Famotidine with Sodium CMC, Carbopol 934P and other excipients.

(Figure 4 and 5)

50.00 100.00 150.00 200.00 250.00 300.00Temp [C]

-30.00

-20.00

-10.00

0.00

mWDSC

167.47 C

Thermal Analysis Result

Figure 4 DSC of Famotidine

50.00 100.00 150.00 200.00 250.00 300.00Temp [C]

-10.00

-5.00

0.00

5.00

mWDSC

164.71 C

249.72 C78.22 C

Thermal Analysis Result

Figure 5 DSC of Formulation



Physicochemical Evaluation of Factorial Batches:

In weight variation test, the Pharmacopoeia limit (IP) for percent of deviation for tablet is

± 7.5%. The average percent deviation of all tablets was found to be within the limit.

Hence, all formulations complies the weight variation test as per IP. All formulations also

comply friability (<1%) and drug content as per IP. All formulations showed tablet

thickness in range of 2.02 to 2.16 mm and surface pH between 6.24 to 6.75 (Table 3).

TABLE 3: PHYSICOCHEMICAL EVALUATION OF FACTORIAL BATCHES

In vitro Dissolution Study:

For investigation purpose 32 full factorial design was chosen to check the effect of

polymer in matrix tablet, in which Ratio of polymer sodium CMC: carbopol 934P as

factor X1 and Concentration of polymer as factor X2 was selected (Table 1). From result

of in vitro release study of 8 hrs of all 9 (F1 to F9) batches it was observed that as there

was increase in concentration of polymer (X2) there was release retarding effect of

concentration of polymer factor (X2). Factor (X1) ratio of polymer had relative effect on

release profile based on fraction of individual polymer. As the fraction of sodium CMC

increases there was more release retardation due to its viscosity building property, it

Batch Thickness Weight

variation Hardness Friability

Drug content

Surface

Code (mm)±SD (mg)±SD (Kg/cm2)±SD (%)±SD (mg)±SD pH±SD

F1 2.08±0.08 149±0.72 5.4±0.25 0.59±0.021 19.81±0.15 6.36±0.058

F2 2.04±0.02 149±0.22 5.5±0.19 0.49±0.032 19.76±0.54 6.52±0.023

F3 2.10±0.11 149±0.24 5.8±0.54 0.46±0.053 19.77±0.34 6.65±0.022

F4 2.04±0.05 148±0.73 5.6±0.64 0.45±0.074 19.91±0.45 6.39±0.034

F5 2.07±0.14 149±0.19 5.5±0.43 0.49±0.021 19.82±0.34 6.65±0.036

F6 2.11±0.04 149±0.49 5.9±0.36 0.62±0.024 19.95±0.25 6.72±0.016

F7 2.02±0.16 150±0.18 6.2±0.42 0.69±0.082 19.94±0.32 6.24±0.022

F8 2.06±0.18 148±0.79 5.7±0.52 0.49±0.015 19.82±0.14 6.41±0.053

F9 2.16±0.19 149±0.84 5.9±0.87 0.72±0.11 19.81±0.09 6.75±0.024



forms viscous gel layer above the mucoadhesive layer of tablet along with carbopol 934P

creating longer diffusion path for drug molecule to diffuse in to dissolution medium

which help in sustained delivery of drug. Lowest release was observed of 77.94% of

batch F9 due to higher concentration of 25% of polymer in ratio of 2:1 (sodium CMC:

carbopol 934P) and highest release of 102.57% was observed in batch F1 with lowest

concentration of 15% of polymer in ratio of 1:2 (Sodium CMC: Carbopol 934P) (Table 4)

(Figure 6 – Figure 12).

TABLE 4: IN VITRO RELEASE DATA OF FACTORIAL BATCHES (N=3)

In vitro release data

Time

(hrs) F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

0.5 19.82 24.27 27.14 26.03 19.64 21.40 20.84 29.18 19.18

1 29.00 29.70 32.23 29.25 28.17 24.85 24.75 35.21 25.57

2 42.35 39.25 41.06 39.17 42.43 35.84 32.50 45.28 34.81

3 52.40 48.90 51.19 49.28 52.57 44.71 43.10 52.02 44.50

4 63.19 59.75 56.78 59.48 58.27 53.30 54.08 56.88 52.16

5 69.92 66.44 68.82 70.16 70.60 61.60 61.09 68.27 62.49

6 79.76 74.59 77.17 77.51 79.81 70.34 69.46 75.60 67.63

7 87.11 82.34 84.58 81.12 85.02 73.43 74.67 82.62 70.23

8 102.57 93.50 86.32 88.11 90.75 78.12 83.16 86.84 77.94

Standard deviation values of all batches are within the limit of ± 5.00%



Figure 6 In vitro dissolution data of factorial batches

Figure 7 Influence of total polymer content on drug release at Sodium CMC to Carbopol 934P

ratio of 1:2




ratio of 1:1


ratio of 2:1



Figure 10 Influence of polymer ratio on drug release at polymer concentration of 15%.





Swelling Index Study:

On swelling index study factor (X2) concentration of polymer has positive effect, as

increase in concentration of polymer there was increase in swelling property of tablet

matrix. Whereas factor (X1) ratio of polymer in ratio of 1:2 and 2:1 of sodium CMC:

carbopol 934P shows higher swelling property than ratio of 1:1. Lowest swelling index

was observed of 54.05% of batch F2 due to lower concentration 15% of polymer in ratio

of 1:1 (sodium CMC : carbopol 934P) and highest swelling index of 100.62% was

observed in batch F9 with higher concentration 25% of polymer in ratio of 2:1 (sodium

CMC : carbopol 934P) (Figure 13).



Figure 13 Swelling index study of factorial batches

Mucoadhesive Strength Study:

On mucoadhesive strength study factor (X2) concentration of polymer has positive effect

as observed in swelling property, as increase in concentration of polymer there was

increase in mucoadhesive strength of tablet. Whereas effect of factor (X1) polymer ratio

on mucoadhesive strength promptly depends on fraction of carbopol 934P in tablet

formulation, as the content of carbopol 934P higher in relation to sodium CMC than there

was higher mucoadhesive strength of tablet due to higher and effective mucoadhesive

property of carbopol 934P. Lowest mucoadhesive strength was observed 9 gm of batch

F3 due to lower concentration of 15% of polymer in ratio of 2:1 (Sodium CMC :

Carbopol 934P) and highest mucoadhesive strength 21 gm was observed in batch F7 with

higher concentration of 25% of polymer in ratio of 1:2 (Sodium CMC: Carbopol 934P)

(Figure 14).



Figure 14 Mucoadhesive strength study of factorial batches

In vitro Residence Time Study:

In vitro residence time of greater than 8 hrs was observed in all of the factorial batches

(F1-F9) (Table 5).

TABLE 5: IN VITRO RESIDENCE TIME STUDY OF FACTORIAL BATCHES

Statistical analysis:

The dependent variables selected in 32 full factorial design were Cumulative percent

release at 4 hour (Q4), Cumulative percent release at 8 hour (Q8), Swelling index (SE),

Mucoadhesive strength (MS), Release rate constant (k) and Diffusion exponent (n) to

study the effect of independent variables X1 (ratio of polymer) and X2 (concentration of

Batch code

Residence time (hrs)

F1 >8 F2 >8 F3 >8 F4 >8 F5 >8 F6 >8 F7 >8 F8 >8 F9 >8



polymer). The results of dependable variables of all F1 to F9 batches were displayed in

(Table 6).

TABLE 6: RESULT OF DEPENDENT VARIABLES FOR FACTORIAL DESIGN

BATCHES

Batch Code

Q4 Q8 Swelling

index Mucoadhesive strength (gm)

Release rate

constant (k)

Diffusion exponent

(n)

F1 63.19 102.57 63.19 14 0.2883 0.5728

F2 59.81 93.50 54.05 11 0.3073 0.4904

F3 56.78 86.32 66.55 9 0.3330 0.4427

F4 59.48 88.11 82.43 19 0.3160 0.4726

F5 58.28 90.75 80.07 16 0.2852 0.5573

F6 53.30 78.12 86.21 13 0.2710 0.5010

F7 54.03 83.16 90.45 21 0.2617 0.5233

F8 56.31 86.84 84.58 18 0.3579 0.4005

F9 52.65 77.94 100.62 16 0.2602 0.5167

TABLE 7: SUMMARY OF RESULTS OF REGRESSION ANALYSIS

Parameter Coefficient of regression parameter

b0 b1 b2 b11 b22 b12 r2 p

Q4 58.061 -2.328 -2.798 -1.562* 0.109* 1.258* 0.946 0.040

CPR 88.540 -5.244 -5.743 -4.327* 2.733* 2.757* 0.940 0.048

% Swelling index

77.120 2.885* 15.310 8.675 -6.330 1.703* 0.987 0.005

Mucoadhesive strength

15.778 -2.667 3.500 0.333* -1.167 0.000* 0.996 0.001

(k) 0.310 -0.000* -0.008* -0.028* 0.011* -0.012* 0.310 0.904*

(n) 0.496 -0.018* -0.011* 0.022* -0.019* 0.031* 0.351 0.872*

*Indicate the value is insignificant at P = 0.05

The value of the correlation coefficients (r2) and P values were reported in table 7

indicated good fit of model for all dependable variables (except k and n).



The fitting equations relating the response to the transformed factor can be shown as

follows.

Q4 = 58.06 - 2.33X1 - 2.80X2 – 1.56 X11 + 0.11 X22 + 1.26 X12

CPR = 88.54 - 5.24 X1 - 5.74 X2 - 4.33 X11 + 2.73 X22 + 2.76 X12

SE = 77.12 + 2.89 X1 + 15.31 X2 + 8.68 X11 - 6.33 X22 + 1.70 X12

BS = 15.78 - 2.67 X1 + 3.50 X2 + 0.33 X11 - 1.17 X22 - 0.00 X12

k = 0.31 – 0.00 X1 – 0.01 X2 - 0.03 X11 + 0.01 X22 - 0.01 X12

n = 0.50 – 0.02 X1 – 0.01 X2 + 0.02 X11 – 0.02 X22 - 0.03 X12

Based on study of magnitude of co-efficient and the mathematical sign it carries, the

above polynomial equation can be used to draw the conclusion regarding the influence of

independent variable on the given dependent variables. The positive and negative values

coefficient of independable variables indicates the change in response of dependable

variable. From result of multiple regression analysis, it was observed that both ratio and

concentration of polymer had statistically significant influence (P<0.05) on all dependent

variables studied except Release rate constant (k), Diffusion exponent (n) and X1 factor in

case of swelling index.

The results depicts (table 5) that dependable variable Q4 and CPR has negative signs of

coefficients of factor X1 and X2 which indicates as there was increase in concentration

and ratio of polymers there was decrease in release of drug at 4 hour and 8 hour

respectively. Independable factor X2 (polymer concentration) has significant effect on

swelling index where as X1 (ratio of polymer) factor has insignificant effect on it. Positive

sign of coefficient of X2 indicates as the polymer concentration increases swelling

property of polymers in matrix tablet increases due to synergistic effect of combination of

polymers Sodium CMC and Carbopol 934P.

Negative sign of X1 Coefficient of bioadhesive strength concludes that as the ratio 1:2 to

2:1 increases there was decrease in bioadhesive strength due to decrease in fraction of

carbopol 934 P in to polymer blend. Where as positive sign of coefficient of X2 conclude

as the concentration increases there was increment in bioadhesive strength. Dependable

variables k and n has insignificant effect of factor X1 and X2 (P>0.05). In all of above



dependable variables interaction between X1 and X2 factors have insignificant effect due

to P>0.05.

Response Surface Plots of Dependable Variables:

From the response surface plot of Q4 and Q8, it was observed that as the level of X2 were

changed from -1 to 1 there was significant decrease in release of drug from matrix due to

increase in the concentration of polymer in the matrix formulation. When levels of X1

changed from -1 to 1 the release is dependent on fraction of sodium CMC in polymer

combination due to formation of highly viscous gel layer on tablet matrix by it which

makes the longer path for diffuse through tablet matrix and hence retards the drug

release. Now in case of response surface of swelling index and mucoadhesive strength

levels of factor X2 changed from -1 to 1 there is increment in both of the response where

as levels of X1 changed from -1 to 1 mucoadhesive strength significantly declines and

swelling index has insignificant effect. Release rate constant (k) and Diffusion exponent

(n) showed insignificant effect to independant variables. (Figure 15).

(A) (B)



(C) (D)

(E) (F)

Figure 15 Response surface plot of dependable variables (A) Q4, (B) Q8, (C) Swelling index, (D)

Mucoadhesive strength, (E) Release rate constant k, (F) Diffusion exponent n.

Kinetic Studies of Factorial Batches:

In order to elucidate the release mechanism the data of factorial batches (F1-F9) were

fitted in to different kinetic models zero order, First order, Higuchi model and Krosmeyer



model. When data fitted into first order model regression co-efficient values were

between 0.9430 to 0.9762 (Table 8) and zero order model regression co-efficient values

were between 0.9898 to 0.9986 (Table 8) which suggests that rate of release from tablet

matrix was followed zero order kinetics. The data fitted with higuchi model with their

regression co-efficient values between 0.9905 to 0.9976 indicating the release of drug

from tablet matrix was diffusion controlled. To know precisely whether Fickian or non-

fickian diffusion was existing, the data was fitted in to krosmeyer model with their

diffusion exponent (n) values ranging between 0.4427 to 0.5728 (Table 8). Out of nine

factorial batches four batches showed “n” values <0.5 which indicates Fickian diffusion

from tablet matrix and another five batches showed “n” values >0.5 which indicates

anamolous diffusion or non Fickian diffusion from tablet matrix. From overall results

majority of batches showed n >0.5 values which indicates non Fickian diffusion from

tablet matrix.

TABLE 8: RESULT OF KINETIC STUDIES OF FACTORIAL BATCHES

Batch code

Zero order First order Higuchi model Krosmeyer

model R2 K R2 K R2 K R2 n

F1 0.9950 10.2669 0.9537 0.0844 0.9926 36.8686 0.9980 0.5728 F2 0.9986 9.0072 0.9762 0.0746 0.9905 32.1608 0.9894 0.4904 F3 0.9940 8.3247 0.9749 0.0675 0.9906 29.8619 0.9862 0.4427 F4 0.9934 8.6372 0.9709 0.0718 0.9922 31.0543 0.9849 0.4726 F5 0.9898 9.3966 0.9430 0.0811 0.9976 34.0910 0.9989 0.5573 F6 0.9916 7.8874 0.9621 0.0750 0.9951 28.4913 0.9913 0.5010 F7 0.9970 8.4590 0.9736 0.0797 0.9908 30.2591 0.9860 0.5233 F8 0.9958 7.7338 0.9761 0.0610 0.9919 27.7279 0.9882 0.4005 F9 0.9898 7.7724 0.9539 0.0762 0.9965 28.1666 0.9967 0.5167

R2: Regression, k: Release rate constant and n: Diffusion exponent. Comparison of Dissolution Profiles For Selection of Optimum Batch:

Ø Similarity factor and Dissimilarity factor:

The values of similarity factor (f2) for the batch F1 showed maximum f2 value 65.76 and

dissimilarity factor (f1) showed minimum f1 value 7.04 as shown in Table 9. Hence,

formulation batch F1 was considered as optimum batch.



TABLE 9: RESULT OF SIMILARITY FACTOR (F2) AND DISSIMILARITY

FACTOR (F1) FOR F1-F9

Batch code Similarity factor (f2)

Dissimilarity factor (f1)

F1 65.76 7.04 F2 64.73 7.11 F3 58.61 8.38 F4 60.86 8.10 F5 62.42 7.91 F6 49.48 11.58 F7 52.56 10.95 F8 54.78 10.52

F9 47.49 12.85 Ex Vivo Permeation Study of Optimized Batch F1:

The result exhibits preliminary batch F1 was permeated 94.70% within 8 hrs (Table 10)

where as in vitro release study showed 102.57% release within 8 hrs (Table 4) which

indicates no significant difference between results of permeation study and in vitro

release study.

TABLE 10: PERMEATION STUDY OF OPTIMIZED BATCH F1

Time (hrs)

% Permeation

0 0.00

0.5 13.74

1 22.65

2 33.84

3 42.35

4 57.62

5 68.47

6 77.86

7 85.39

8 94.70

Results of Accelerated Stability Study:

In order to determine the change in in vitro release profile on storage, stability study of

formulation F1 was carried out at 40°C in a humidity jar having 75 % RH. Samples

evaluated after one month showed no change in in vitro drug release pattern as shown in



Table 5.21. The value of similarity factor (f2) was 89.65 and dissimilarity factor (f1)

(Table 11) (Figure 16) indicating good similarity of dissolution profiles before and after

stability studies.

TABLE 11: IN VITRO DISSOLUTION DATA OF BATCH F1 AFTER

ACCELERATED STABILITY STUDY

Time (hrs)

CPR (Initial)

CPR (After storage at

40o C for 1month)

0 0.00 0.00

0.5 19.82 19.82

1 29.00 28.08

2 42.35 41.97

3 52.40 51.36

4 63.19 62.15

5 69.92 68.77

6 79.76 78.42

7 87.11 86.49

8 102.57 100.10

f1 Value Reference 1.70

f2 Value Reference 89.65

Figure 16



In vitro dissolution profile of batch F1 after accelerated stability study

CONCLUSION

In present investigation, attempt has been made to develop mucoadhesive buccal tablet of

Famotidine by using polymer combination for sustained delivery upto 8 hrs. The

influence of ratio of Sodium carboxy methyl cellulose and Carbopol 934P and polymer

concentration on kinetics was studied using 32 full factorial design. The ratio of polymer

and concentration of polymer both have simultaneous release retarding effect. Here

formulation gives sustained release due formation of viscous gel layer above the

mucoadhesive layer of tablet due to viscosity building property of Sodium CMC, which

makes longer path for drug to diffuse from the mucoadhesive layer in to the dissolution

medium. This combination of this polymer allowed formation of a tougher, denser gelled

structure and served as a physical barrier to drug diffusion, resulting in a decrease in drug

release. It was concluded that for the development of sustained release mucoadhesive

buccal tablet formulation of Famotidine, role of ratio of polymer and content of polymer

appears necessary. Formulation F1 was selected as an optimum formulation as it shows

more similarity in dissolution profile with theoretical profile (Similarity factor, f2=65.76

and Dissimilarity factor, f1=7.04). The optimized formulation (Batch F1) had given

release of 102.57% in 8hrs and it had optimum swelling and mucoadhesive property. The

optimized formulation had desired drug release kinetics and found to be stable for the

period of 1 month.

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For Correspondence: Jalpeshkumar D. Bhavsar Email: [email protected]

Documents

FORMULATION AND IN-VITRO EVALUATION OF · PDF fileJalpeshkumar D. Bhavsar*, Mukesh R. Patel, Kanu R. Patel, N.M.Patel Shri B. M. Shah College of Pharmaceutical Education & Research,